Biology subjects

Pearson, J.

Publications and source records attributed to Pearson, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2021

Encoding of odors by mammalian olfactory receptors

O_LIIdentified ligands for > 500 mouse ORs C_LIO_LIORs are specifically tuned towards individual odorants and their molecular properties C_LIO_LIOdor molecular properties are informative of odor responses C_LIO_LIPredictive modeling and convergent evolution analyses suggest specific residues within a canonical location for odorant binding C_LI Olfactory receptors (ORs) constitute the largest multi-gene family in the mammalian genome, with hundreds to thousands of loci in humans and mice respectively1. The rapid expansion of this massive family of genes has been generated by numerous duplication and diversification events throughout evolutionary history. This size, similarity, and diversity has made it challenging to define the principles by which ORs encode olfactory stimuli. Here, we performed a broad surveying of OR responses, using an in vivo strategy, against a diverse panel of odorants. We then used the resulting interaction profiles to uncover relationships between OR responses, odorants, odor molecular properties, and OR sequences. Our data and analyses revealed that ORs generally exhibited sparse tuning towards odorants and their molecular properties. Odor molecular property similarity between pairs of odorants was informative of odor response similarity. Finally, ORs sharing response to an odorant possessed amino acids at poorly conserved sites that exhibited both, predictive power towards odorant selectivity and convergent evolution. The localization of these residues occurred primarily at the interface of the upper halves of the transmembrane domains, implying that canonical positions govern odor selectivity across ORs. Altogether, our results provide a basis for translating odorants into receptor neuron responses for the unraveling of mammalian odor coding.

neuroscience↗

bioRxiv2021

The eyes have it: The pupillary light response as a physiological index of aphantasia, sensory and phenomenological imagery strength

The pupillary light response is an important automatic physiological response that optimises light reaching the retina. Recent work has shown that the pupil also adjusts in response to illusory brightness and a range of cognitive functions, however, it remains unclear what exactly drives these endogenous changes. Here we show that the imagery pupillary light response correlates with objective measures of sensory imagery strength. Further, the trial-by-trial phenomenological vividness of visual imagery is tracked by the imagery pupillary light response. We also demonstrated that there was no evidence for an imagery pupillary light response in a group of individuals without visual imagery (aphantasia), however, they did show perceptual pupil light responses and pupil dilation with larger cognitive load. Our results provide evidence that the pupillary light response indexes the sensory strength of visual imagery and also provides the first physiological validation of aphantasia.

neuroscience↗

bioRxiv2021

Impact of sulfamethoxazole on a riverine microbiome

The continued emergence of bacterial pathogens presenting antimicrobial resistance is widely recognised as a global health threat and recent attention focused on potential environmental reservoirs of antibiotic resistance genes (ARGs). Freshwater environments such as rivers represent a potential hotspot for ARGs and antibiotic resistant bacteria as they are receiving systems for effluent discharges from wastewater treatment plants (WWTPs). Effluent also contains low levels of different antimicrobials including antibiotics and biocides. Sulfonamides are antibacterial chemicals widely used in clinical, veterinary and agricultural settings and are frequently detected in sewage sludge and manure in addition to riverine ecosystems. The impact of such exposure on ARG prevalence and diversity is unknown, so the aim of this study was to investigate the release of a sub-lethal concentration of the sulfonamide compound sulfamethoxazole (SMX) on the river bacterial microbiome using a flume system. This system was a semi-natural in vitro flume using river water (30 L) and sediment with circulation to mimic river flow. A combination of omics approaches were conducted to study the impact of SMX exposure on the microbiomes within the flumes. Metagenomic analysis showed that the addition of low concentrations of SMX (<4 g L-1) had a limited effect on the bacterial resistome in the water fraction only, with no impact observed in the sediment. Metaproteomics did not show differences in ARGs expression with SMX exposure in water. Overall, the river bacterial community was resilient to short term exposure to sub-lethal concentrations of SMX which mimics the exposure such communities experience downstream of WWTPs throughout the year.

microbiology↗

bioRxiv2021

The inflammasome-activated cytokine IL-1 is targeted for ubiquitylation and proteasomal degradation to limit its inflammatory potential

Interleukin-1{beta} (IL-1{beta}) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in wide-spread diseases. Therefore, IL-1{beta} activity must be fine-tuned to enable antimicrobial responses whilst limiting collateral damage. Here we report that precursor IL-1{beta} is rapidly turned over by the proteasome and this correlates with its decoration by K11-, K63- and K48-linked ubiquitin chains. The ubiquitylation of IL-1{beta} is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1{beta} cleavage by caspase-1. We further demonstrate that IL-1{beta} K133 is modified by ubiquitin and forms a salt bridge with IL-1{beta} D129. Loss of IL-1{beta} K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1{beta}. Accordingly, IL-1{beta}K133R/K133R mice display increased precursor IL-1{beta} upon inflammasome priming and increased bioactive IL-1{beta}, both in vitro and following LPS injection in vivo. These findings reveal new mechanisms for limiting IL-1{beta} activity and safeguarding against damaging inflammation.

immunology↗

bioRxiv2020

Variable expression quantitative trait loci analysis of breast cancer risk variants

Genome wide association studies (GWAS) have identified more than 180 variants associated with breast cancer risk, however the underlying functional mechanisms and biological pathways which confer disease susceptibility remain largely unknown. As gene expression traits are under genetic regulation we hypothesise that differences in gene expression variability may identify causal breast cancer susceptibility genes. We performed variable expression quantitative trait loci (veQTL) analysis using tissue-specific expression data from the Genotype-Tissue Expression (GTEx) Common Fund Project. veQTL analysis identified 70 associations (p < 5x10-8) consisting of 60 genes and 27 breast cancer risk variants, including 55 veQTL that were observed in breast tissue only. Pathway analysis of genes associated with breast-specific veQTL revealed an enrichment of four genes (CYP11B1, CYP17A1 HSD3B2 and STAR) involved in the C21-steroidal biosynthesis pathway that converts cholesterol to breast-related hormones (e.g. oestrogen). Each of these four genes were significantly more variable in individuals homozygous for rs11075995 (A/A) breast cancer risk allele located in the FTO gene, which encodes an RNA demethylase. The A/A allele was also found associated with reduced expression of FTO, suggesting an epi-transcriptomic mechanism may underlie the dysregulation of genes involved in hormonal biosynthesis leading to an increased risk of breast cancer. These findings provide evidence that genetic variants govern high levels of expression variance in breast tissue, thus building a more comprehensive insight into the underlying biology of breast cancer risk loci.

cancer biology↗

bioRxiv2020

APC Mutation marks an aggressive subtype of BRAF mutant colorectal cancers that are associated with early-onset and dismal prognosis

Background & AimsWNT activation is a hallmark of colorectal cancer. BRAF mutation is present in 15% of colorectal cancers, and the role of mutations in WNT signaling regulators in this context is unclear. Here we evaluate the mutational landscape of WNT signaling regulators in BRAF mutant cancers. MethodsWe performed exome-sequencing on 24 BRAF mutant colorectal cancers and analysed these data in combination with 175 publicly available BRAF mutant colorectal cancer exomes. We assessed the somatic mutational landscape of WNT signaling regulators, and performed hotspot and driver mutation analyses to identify potential drivers of WNT signaling. The effects of Apc and Braf mutation were modelled, in vivo, using the Apcmin/+ and BrafV637/Villin-CreERT2/+ mouse, respectively. ResultsRNF43 was the most frequently mutated WNT signaling regulator (41%). Mutations in the beta-catenin destruction complex occurred in 48% of cancers. Hotspot analyses identified potential cancer driver genes in the WNT signaling cascade, including MEN1, GNG12 and WNT16. Truncating APC mutation was identified in 20.8% of cancers. Truncating APC mutation was associated with early age at diagnosis (P< 2x10-5), advanced stage (P<0.01), and poor survival (P=0.026). Apcmin/+/BrafV637 animals had more numerous and larger SI and colonic lesions (P<0.0001 and P<0.05, respectively), and a markedly reduced survival (Median survival: 3.2 months, P=8.8x10-21) compared to animals with Apc or Braf mutation alone. ConclusionsThe WNT signaling axis is frequently mutated in BRAF mutant colorectal cancers. WNT16 and MEN1 may be novel drivers of aberrant WNT signaling in colorectal cancer. Co-mutation of BRAF and APC generates an extremely aggressive neoplastic phenotype that is associated with poor patient outcome. SynopsisWe have comprehensively evaluated the somatic mutation landscape of WNT signaling regulators in serrated colorectal cancers. We identified a mosaic of mutations that may be responsible for elevating WNT signaling in this context. Approximately 20% of serrated colorectal cancers harbor truncating APC mutation, and these cancers confer extremely poor prognoses.

cancer biology↗

bioRxiv2020

Decoding non-conscious thought representations during successful thought suppression

Controlling our own thoughts is central to mental wellbeing and its failure is at the crux of a number of mental disorders. Paradoxically, behavioural evidence shows that thought-suppression often fails. Despite the broad importance of understanding the mechanisms of thought control, little is known about the fate of neural representations of suppressed thoughts. Using functional MRI, we investigated the brain areas involved in controlling visual thoughts and tracked suppressed thought representations using multi-voxel pattern analysis (MVPA). Participants were asked to either visualize a vegetable/fruit or suppress any visual thoughts about those objects. Surprisingly, the content (object identity) of successfully suppressed thoughts was still decodable in visual and executive areas with algorithms trained on perception or imagery. This suggests that pictorial representations of the suppressed thoughts are still present despite individuals reporting they are not. Thought generation was associated with the left hemisphere, whereas thought suppression with right hemisphere engagement. Further, GLM analyses showed that subjective success in thought suppression was correlated with engagement of executive areas, while thought-suppression failure was associated with engagement of visual and memory related areas. These results reveal that the content of suppressed thoughts exist hidden from awareness, seemingly without an individuals knowledge, providing a compelling reason why thought suppression is so ineffective. These data inform models of unconscious thought production and could be used to develop new treatment approaches to disorders involving maladaptive thoughts.

neuroscience↗

bioRxiv2019

Circuit and synaptic organization of forebrain-to-midbrain pathways that promote and suppress vocalization

Animals vocalize only in certain behavioral contexts, but the circuits and synapses through which forebrain neurons trigger or suppress vocalization remain unknown. Here we used transsynaptic tracing to identify two populations of inhibitory neurons that lie upstream of neurons in the periaqueductal gray that gate the production of ultrasonic vocalizations in mice (i.e., PAG-USV neurons). Activating PAG-projecting neurons in the preoptic hypothalamus (POAPAG neurons) elicited USV production in the absence of social cues. In contrast, activating PAG-projecting neurons in the central-medial boundary zone of the amygdala (AmgC/M-PAG neurons) transiently suppressed USV production without disrupting non-vocal social behavior. Optogenetics-assisted circuit mapping in brain slices revealed that POAPAG neurons directly inhibit PAG interneurons, which in turn inhibit PAG-USV neurons, whereas AmgC/M-PAG neurons directly inhibit PAG-USV neurons. These experiments identify two major forebrain inputs to the PAG that trigger and suppress vocalization, respectively, while also establishing the synaptic mechanisms through which these neurons exert opposing behavioral effects.

neuroscience↗

bioRxiv2019

Regulatory T cell expansion by a highly CD25-dependent IL-2 mutein arrests ongoing autoimmunity

Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T cells (Tregs) and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2-based therapeutics with improved Treg-specificity. From a panel of rationally designed IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg-selectivity due to increased dependence on the IL-2-receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared to Fc-fused wild-type IL-2. Preferential Treg enrichment was also observed in the presence of activated pathogenic T cells in the autoimmune target organ, despite a loss of Treg-selectivity in an IL-2R-proximal response. These features allowed for extended resolution of spontaneous autoimmunity using infrequent dosing schedules. Thus, IL-2 muteins enable efficient, flexible, and targeted control of the autoimmune response. One Sentence SummaryA CD25-dependent IL-2 mutein selectively expands regulatory T cells and provides potent and targeted control of autoimmunity.

immunology↗

bioRxiv2019

Inferring low-dimensional latent descriptions of animal vocalizations

Increases in the scale and complexity of behavioral data pose an increasing challenge for data analysis. A common strategy involves replacing entire behaviors with small numbers of handpicked, domain-specific features, but this approach suffers from several crucial limitations. For example, handpicked features may miss important dimensions of variability, and correlations among them complicate statistical testing. Here, by contrast, we apply the variational autoencoder (VAE), an unsupervised learning method, to learn features directly from data and quantify the vocal behavior of two model species: the laboratory mouse and the zebra finch. The VAE converges on a parsimonious representation that outperforms handpicked features on a variety of common analysis tasks, enables the measurement of moment-by-moment vocal variability on the timescale of tens of milliseconds in the zebra finch, provides strong evidence that mouse ultrasonic vocalizations do not cluster as is commonly believed, and captures the similarity of tutor and pupil birdsong with qualitatively higher fidelity than previous approaches. In all, we demonstrate the utility of modern unsupervised learning approaches to the quantification of complex and high-dimensional vocal behavior.

animal behavior and cognition↗

bioRxiv2019

Single-cell analysis of human retina identifies evolutionarily conserved and species-specific mechanisms controlling development.

The development of single-cell RNA-Sequencing (scRNA-Seq) has allowed high resolution analysis of cell type diversity and transcriptional networks controlling cell fate specification. To identify the transcriptional networks governing human retinal development, we performed scRNA-Seq over retinal organoid and in vivo retinal development, across 20 timepoints. Using both pseudotemporal and cross-species analyses, we examined the conservation of gene expression across retinal progenitor maturation and specification of all seven major retinal cell types. Furthermore, we examined gene expression differences between developing macula and periphery and between two distinct populations of horizontal cells. We also identify both shared and species-specific patterns of gene expression during human and mouse retinal development. Finally, we identify an unexpected role for ATOH7 expression in regulation of photoreceptor specification during late retinogenesis. These results provide a roadmap to future studies of human retinal development, and may help guide the design of cell-based therapies for treating retinal dystrophies.

neuroscience↗

bioRxiv2019

The critical role of mental imagery in human emotion: insights from Aphantasia.

One proposed function of imagery is to make thoughts more emotionally evocative through sensory simulations. Here we report a novel test of this theory utilizing a special population with no visual imagery: Aphantasia. After using multi-method verification of aphantasia, we show that this condition, but not the general population, is associated with a flat-line physiological response to frightening written, but not perceptual scenarios, supporting imagerys critical role in emotion.

neuroscience↗

bioRxiv2019

Functional harmonics reveal multi-dimensional basis functions underlying cortical organization

The human brain consists of functionally specialized areas, which flexibly interact and integrate forming a multitude of complex functional networks. However, the nature and governing principles of these specialized areas remain controversial: a distinct modular architecture versus a smooth continuum across the whole cortex. Here, we demonstrate a candidate governing principle ubiquitous in nature, that resolves this controversy for the brain at rest, during perception, cognition and action: functional harmonic modes. We calculated the harmonic modes of the brains functional connectivity, called "functional harmonics", from functional magnetic resonance imaging (fMRI) data in resting state of 812 participants. Each functional harmonic provides an elementary pattern of brain activity with a different spatial frequency. The set of all functional harmonics - ordered according to their spatial frequencies - can reconstruct any pattern of brain activity. The activity patterns elicited by 7 different tasks from the Human Connectome Project can be reconstructed from a very small subset of functional harmonics, suggesting a novel relationship between task and resting state brain activity. Further, the isolines of the continuous functional harmonic patterns delineate the borders of specialized cortical areas as well as somatotopic and retinotopic organization. Our results demonstrate a candidate scalable governing principle for functional brain organization, resolving the controversy between modular versus gradiental views, and demonstrate that a universal principle in nature also underlies human brain cortical organization.

neuroscience↗

bioRxiv2019

MinION Sequencing of colorectal cancer tumour microbiomes - a comparison with amplicon-based and RNA-Sequencing

Recent evidence suggests a role for the gut microbiome in the development and progression of colorectal cancer. In this study we compare MinION sequencing with meta-transcriptomics and amplicon-based sequencing for microbiome analysis of colorectal tumour tissue samples. DNA and RNA were extracted from 11 colorectal tumour samples. RNA-Sequencing, 16S rRNA amplicon sequencing and MinION genomic sequencing was carried out and resulting data used as input for taxonomic classification using Kraken2. Taxonomic concordance between the three platforms at different taxonomic levels was tested on a per sample basis. The average number of reads per sample using RNA-Sequencing was more than 129 times that generated using MinION sequencing. However, the average read length of MinION sequences was more than 13 times that of RNA or 16S rRNA amplicon sequencing. 16S sequencing was less informative beyond the genus level, and both RNA-Sequencing and MinION sequencing could detect more phyla and genera in the same samples, compared to 16S sequencing. Long-read sequences generated using MinION sequencing can compensate for low numbers of reads for bacterial classification. MinION sequencing can discriminate between bacterial strains and plasmids and shows potential as a tool for microbiome sequencing of colorectal cancers in a clinical setting.

microbiology↗

bioRxiv2018

Late Pleistocene human genome suggests a local origin for the first farmers of central Anatolia

Anatolia was home to some of the earliest farming communities. It has been long debated whether a migration of farming groups introduced agriculture to central Anatolia. Here, we report the first genome-wide data from a 15,000-year-old Anatolian hunter-gatherer and from seven Anatolian and Levantine early farmers. We find high genetic continuity ([~]80-90%) between the hunter-gatherer and early farmers of Anatolia and detect two distinct incoming ancestries: an early Iranian/Caucasus related one and a later one linked to the ancient Levant. Finally, we observe a genetic link between southern Europe and the Near East predating 15,000 years ago that extends to central Europe during the post-last-glacial maximum period. Our results suggest a limited role of human migration in the emergence of agriculture in central Anatolia.

genetics↗

bioRxiv2018

Genome Scale Epigenetic Profiling Reveals Five Distinct Subtypes of Colorectal Cancer

BACKGROUNDColorectal cancer is an epigenetically heterogeneous disease, however the extent and spectrum of the CpG Island Methylator Phenotype (CIMP) is not clear.\n\nRESULTSAn unselected cohort of 216 colorectal cancers clustered into five clinically and molecularly distinct subgroups using Illumina 450K DNA methylation arrays. CIMP-High cancers were most frequent in the proximal colons of female patients. These dichotomised into CIMP-Hl and CIMP-H2 based on methylation profile which was supported by over representation of BRAF (74%, P<0.0001) or KRAS (55%, P<0.0001) mutation, respectively. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CI MP-Negative subgroup to 75 years in the CIMP-Hl subgroup (P<0.0001). There was a striking association between PRC2-marked loci and those subjected to significant gene body methylation in CIMP-type cancers (P<1.6xl078). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster specific mutations were observed for genes involved in chromatin remodelling, such as in the SWI/SNF and NuRD complexes, suggesting synthetic lethality.\n\nCONCLUSIONThere are five clinically and molecularly distinct subgroups of colorectal cancer based on genome wide epigenetic profiling. These analyses highlighted an unidentified role for gene body methylation in progression of serrated neoplasia. Subgroup-specific mutation of distinct epigenetic regulator genes revealed potentially druggable vulnerabilities for these cancers, which may provide novel precision medicine approaches.

genomics↗

bioRxiv2018

Bayesian Nonparametric Models Characterize Instantaneous Strategies in a Competitive Dynamic Game

Previous approaches to investigating strategic social interaction in game theory have predominantly used games with clearly-defined turns and limited choices. However, most real-world social behaviors involve dynamic, coevolving decisions by interacting agents, which pose challenges for creating tractable models of behavior. Here, using a competitive game in which human participants control the dynamics of an on-screen avatar against either another human or a computer opponent, we show that it is possible to quantify the dynamic coupling between agents using nonparametric models. We use Gaussian Processes to model the joint distributions of players' actions and identities (human or computer) as a function of game state. Borrowing from a reinforcement learning framework, we successfully approximated both the policy and the value functions used by each human player in this competitive context. This approach offers a natural set of metrics for facilitating analysis at multiple timescales and suggests new classes of tractable paradigms for assessing human behavior.

neuroscience↗

bioRxiv2018

Salmonella effectors SseK1 and SseK3 target death domain proteins in the TNF and TRAIL signaling pathways

Strains of Salmonella utilise two distinct type three secretion systems to deliver effector proteins directly into host cells. The Salmonella effectors SseK1 and SseK3 are arginine glycosyltransferases that modify mammalian death domain containing proteins with N-acetyl glucosamine (GlcNAc) when overexpressed ectopically or as recombinant protein fusions. Here, we combined Arg-GlcNAc glycopeptide immunoprecipitation and mass spectrometry to identify host proteins GlcNAcylated by endogenous levels of SseK1 and SseK3 during Salmonella infection. We observed that SseK1 modified the mammalian signaling protein TRADD, but not FADD as previously reported. Overexpression of SseK1 greatly broadened substrate specificity, while ectopic co-expression of SseK1 and TRADD increased the range of modified arginine residues within the death domain of TRADD. In contrast, endogenous levels of SseK3 resulted in modification of the death domains of receptors of the mammalian TNF superfamily, TNFR1 and TRAILR, at residues Arg376 and Arg293 respectively. Structural studies on SseK3 showed that the enzyme displays a classic GT-A glycosyltransferase fold and binds UDP-GlcNAc in a narrow and deep cleft with the GlcNAc facing the surface. Together our data suggests that Salmonellae carrying sseK1 and sseK3 employ the glycosyltransferase effectors to antagonise different components of death receptor signaling.

microbiology↗